A Game of Clones: tracing the roots of therapy-induced hematopoietic evolution

Survival rates for children with cancer have improved substantially over recent decades, reaching a five-year survival of more than 80%. However, this prognosis is accompanied by an increased risk of late effects, including cardiovascular disease and therapy-related second cancers, which contribute to elevated long-term mortality. During ageing and because of cancer treatment, mutations accumulate in cellular DNA. By characterizing these mutations in individual cells, the evolutionary history of second cancers can be reconstructed. To this end, this thesis first describes current knowledge on the detection and accumulation of mutations in healthy tissues, followed by a detailed protocol for one of these methods. These approaches are then applied to investigate the development of second cancers in the blood during initial cancer treatment, the subsequent disease-free period, and at the time of diagnosis of the second cancer.

The results show that variation in mutation burden after chemotherapy can be partially explained by differences between stem cell types and by the elimination of damaged cells through programmed cell death. In contrast to chemotherapy, stem cell transplantation does not increase mutation rates; however, the transplantation process exerts strong selective pressure on cells harboring pre-existing cancer-driving mutations. Finally, this thesis demonstrates that inherited predisposition, such as germline mutations in the TP53 gene, plays an important role in how treatment influences the evolution of second cancers. These findings provide a basis for developing treatment and surveillance strategies aimed at reducing the long-term effects of childhood cancer.